The objectives of this revision application are to identify and characterize craniofacial (CF) disorders in mice that are reliable genetic and physiological models for human craniofacial dysmorphologies and to share these models with the scientific public. Discovery of the genetic cause of CF disease in human populations is difficult due to extreme heterogeneity in humans and to the diversity of environmental and nutritional variables, all of which have a role in resulting CF diseases. Consequently, animal models with defined genetic backgrounds maintained in controlled environments are important for CF gene discovery. The goal of this revision application is to support CF research by providing new mouse models of CF dysmorphologies to FaceBase investigators, and the broader CF research community, via the FaceBase Mouse Repository. Utilizing our well- established program to screen for phenotypic deviants in The Jackson Laboratory's large breeding and research colonies, our ongoing ENU mutagenesis program, and access to newly developed strains via our participation in the NIH-wide Knockout Mouse Phenotyping Program (KOMP2), we will identify, characterize phenotypically and genetically, and distribute novel mouse models of CF disorders. These will include the full range of CF phenotypes, including defects in skull morphology, dentition, vision, and hearing as well as models of orofacial clefting For most models, we will identify the causative gene using high throughput sequencing technologies. Together, the models within this resource will provide critical tools for understanding the basis of CF disorders in humans. ! PUBLIC HEALTH RELEVANCE: Craniofacial disorders are apparent in approximately 1 in 800 live births, representing nearly 75% of all human congenital malformations visible in newborns. This highly diverse group of disorders may include one or more malformations such as cleft lip and palate, abnormal morphology of the skull, face, or jaws, misshapen or missing teeth, and eye and ear abnormalities, with or without impaired sight or hearing. Causes for these disorders have been found to be both genetic and environmental, or the result of interaction between the two. Discovery of the genetic cause of disease in human populations is difficult due to extreme heterogeneity in humans and to the diversity of environmental and nutritional variables. Consequently, animal models with defined genetic backgrounds maintained in controlled environments are of particular importance for craniofacial gene discovery. The research in this project will provide new mouse models for specific craniofacial disorders and for basic research to understand biological systems that regulate the formation of the skull and face. Mouse models enable scientists to understand the causes and pathologies of similar human phenotypes so that prevention strategies or therapeutics can be developed. In addition, therapies or drugs can be tested on mouse models prior to human trials to assess efficacy and safety.